Tetrahydrocarbazole 1-alkanoic acids and pharmaecutical compositions

ABSTRACT

Tetrahydrocarbazole 1-alkanoic acids are disclosed. The compounds act as prostaglandin and thromboxane antagonists and are useful in treating asthma, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion and dysmenorrhea and as cytoprotective agents.

RELATED CASES

This is a division of Ser. No. 076,424, Jul. 21, 1987, U.S. Pat. No. 4,808,608, which is a continuation-in-part of Ser. No. 001,739, Jan. 9, 1987, abandoned, which is a continuation-in-part of Ser. No. 821,726, Jan. 23, 1986, abandoned.

BACKGROUND OF THE INVENTION

This invention relates to prostaglandin antagonists useful in treating a variety of conditions, such as allergic asthma where excessive contractile activity of prostaglandins and prostaglandin biosynthetic intermediates occur.

These compounds antagonize the actions of contractile prostaglandins, such as PGF₂α, PGG₂, PGH₂, PGD₂ and TXA₂. The use of agents which act as prostaglandin antagonists offers new approaches to therapy in a number of disease states. For example, certain prostaglandins, such as PGF₂α, PGD₂, PGG₂, and PGH₂, are potent bronchospastic agents. Indeed human asthmatics have been shown to be especially sensitive to the bronchial constricting action of PGF₂α.

DESCRIPTION OF THE INVENTION

The present invention relates to novel comPounds of Formula I: ##STR1## wherein:

R¹, R², R³, R⁴, R⁵ and R⁶ are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) alkenyl having 2 to 6 carbon atoms;

(4) --(CH₂)_(n) M

wherein n is 0 to 3 and M is

a) OR¹³ ;

b) halogen;

c) CF₃ ;

d) SR¹³ ;

e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of

f) COOR¹⁴ ;

g) ##STR2## h) tetrazole; i) ##STR3## wherein R¹⁶ is C₁ to C₆ alkyl, benzyl or phenyl; j) --NR¹⁴ R¹⁴ ;

k) --NHSO₂ R¹⁷ wherein R¹⁷ is C₁ to C₆ alkyl, 4-methylphenyl, phenyl, or CF₃ ;

l) ##STR4## m) --SOR¹³ ; n) --CONR¹⁴ R¹⁴ ;

o) --SO₂ NR¹⁴ R¹⁴ ;

p) --SO₂ R¹³ ;

q) NO₂ ;

r) ##STR5## s) ##STR6## t) ##STR7## v) N₃ ; u) CN;

R⁷ is H or alkyl of 1 to 6 carbons;

R⁸ is H or alkyl of 1 to 6 carbon atoms;

each R⁹ is independently H, OH, C₁ to C₄ -0-alkyl or alkyl of 1 to 4 carbons;

R¹⁰ is COOH; CH₂ OH; CHO; tetrazole; NHSO₂ R¹¹ wherein R¹¹ is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or to 1 to 6 carbons; CONHSO₂ R¹¹ ; hydroxymethylketone; CN; or CON(R⁹) ;

r is 1 to 6;

each R¹³ independently is H; C₁ to C₆ alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C₁ to C₃ alkyl, halogen, CN, CF₃, COOR¹⁴, CH₂ COOR¹⁴, C₁ to C₃ alkoxy, or C₁ to C₄ perfluoroalkyl;

each R¹⁴ is independently H, phenyl, benzyl or C₁ to C₆ alkyl; and,

each R¹⁵ independently is H, (CH₂)_(m) COOR¹⁴ wherein m is 0 to 4, C₁ to C₆ alkyl, CF₃, phenyl, or substituted phenyl wherein substituted phenyl is as defined above in the definition of R¹³ ;

or a pharmaceutically acceptable salt thereof.

Preferred compounds of the present invention comprise the compounds of formula I wherein:

R¹, R², R³, R⁴, R⁵ and R⁶ are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) alkenyl having 2 to 6 carbon atoms;

(4) --(CH₂)_(n) M

wherein n is 0 or 1 and M is as defined previously for Formula I;

R¹⁰ is COOH; CH₂ OH; CHO; tetrazole; CONHSO_(s) R¹¹ wherein R¹¹ is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 carbons; hydroxymethylketone; CN; or CON(R⁹) ;

r is 1 to 6; and the remaining substituents are as defined previously for Formula I.

More preferred compounds of the present invention comprise the compounds of Formula I. wherein:

R¹, R², R³, R⁴, R⁵ and R⁶ are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) alkenyl having 2 to 6 carbon atoms;

(4) M wherein M is as defined initially for Formula I;

R¹⁰ is COOH; CH₂ OH; CHO; tetrazole; hydroxymethylketone;

r is 1 or 2; and the remaining substituents are as defined initially for Formula I.

Most preferred compounds of the present invention comprise the compounds of Formula I. wherein:

R¹, R², R³, R⁴, R⁵ and R⁶ are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) M wherein M is

a) OR¹³ ;

b) halogen;

c) CF₃ ;

d) SR¹³ ;

e) COOR¹⁴ ;

f) ##STR8## g) tetrazole; h) --SOR¹³ ;

i) --CONR¹⁴ R¹⁴ ;

j) --SO₂ NR¹⁴ R¹⁴ ;

k) --SO₂ R¹³ ;

l) ##STR9## m) CN; n) N₃ ;

each R⁹ is independently H, or alkyl of 1 to 4 carbons;

R¹⁰ is COOH; or tetrazole;

r is 1 and the remaining substituents are as defined initially for Formula I.

In the above most preferred embodiment, those compounds are particularly preferred wherein at least one of R¹ to R⁴ is not hydrogen; one of R⁵ or R⁶ is not hydrogen; R⁷ is hydrogen; R⁹ is hydrogen, and the remaining substituents are as defined in the most preferred embodiment. 

What is claimed is:
 1. A compound of the formula: ##STR10## wherein: R¹ is H, C₁ -C₆ alkyl, OR¹³, F, Cl, or Br;R² is H, Cl, F, or Br; R⁵ is H, Cl, or OR¹³ ; R⁶ is H or Cl; R⁸ is H or C₁ -C₆ alkyl; R¹³ is C₁ -C₆ alkyl; s is 0 when R¹ is C₁ -C₆ alkyl or OR¹³ ; s is 1 when R¹ is H, F, Cl, or Br; t is 0 when R⁵ is OR¹³ ; t is 1 when R⁵ is H or Cl;or a pharmaceutically acceptable salt thereof.
 2. Compound of claim 1 which is:9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-6-methoxy-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (-)9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (+)9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-benzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-methoxybenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-(3,4-dichloro)benzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-[1-(1-phenyl)ethyl]-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-6-chloro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 6-bromo-9-p-chlorobenzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-6-methyl-1,2,3,4-tetrahydrocarbazol-1-yl acetic acid; 9-p-chlorobenzyl-8-fluoro-1,2,3,4-tetrahydrocarbozol-1-yl-acetic acid; 9-p-chlorobenzyl-5-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-7-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-5,7-dichloro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-6,8-dichloro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-6-isopropyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-6-tert-butyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-8-isopropyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (-)-9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (+)-9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (-)-9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (+)-9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (-)-9-p-chlorobenzyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (+)-9-p=chlorobenzyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-o-chlorobenzyl-6,8-difluoro-1,2,3,4-atetrahydrocarbazol-1-yl-acetic acid; 9-(2,4-dichlorobenzyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-m-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid.
 3. A compound of claim 1 which is:9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; 9-p-chlorobenzyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; or 9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid.
 4. A compound of claim 1, which is a pure optical isomer.
 5. A compound of claim 4, which is the (+)-isomer.
 6. A compound of claim 4, which is the (-)-isomer.
 7. A compound of claim 6 which is:(-)9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (-)-9-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (-)-9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; or (-)-9-p-chlorobenzyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid.
 8. A compound of the formula: ##STR11## wherein:

    ______________________________________                                         Compound                                                                               R.sup.1      R.sup.2                                                                               R.sup.5                                                                               R.sup.6                                                                              R.sup.8                               ______________________________________                                         1 (Ex. 1)                                                                              6-F          H      4'-Cl  H     H                                     2 (Ex. 4)                                                                              6-OMe        H      4'-Cl  H     H                                     3 (Ex. 7)                                                                              6-F (-)isomer                                                                               H      4'-Cl  H     H                                     4 (Ex. 8)                                                                              6-F (+)isomer                                                                               H      4'-Cl  H     H                                     5 (Ex. 9)                                                                              6-F          H      H      H     H                                     6 (Ex. 10)                                                                             6-F          H      4'-OMe H     H                                     7 (Ex. 11)                                                                             6-F          H      3'-Cl  4'-Cl H                                     8 (Ex. 12)                                                                             6-F          H      H      H     Me                                    9 (Ex. 13)                                                                             H            H      4'-Cl  H     H                                     10 (Ex. 14)                                                                            6-Cl         H      4'-Cl  H     H                                     11 (Ex. 15)                                                                            8-Me         H      4'-Cl  H     H                                     12 (Ex. 16)                                                                            6-Br         H      4'-Cl  H     H                                     13 (Ex. 17)                                                                            6-Me         H      4'-Cl  H     H                                     14 (Ex. 19)                                                                            8-F          H      4'-Cl  H     H                                     16 (Ex. 21)                                                                            5-F          H      4'-Cl  H     H                                     17 (Ex. 21)                                                                            7-F          H      4'-Cl  H     H                                     18 (Ex. 22)                                                                            5-Cl         7-Cl   4'-Cl  H     H                                     19 (Ex. 23)                                                                            6-Cl         8-Cl   4'-Cl  H     H                                     23      8-Br         H      4'-Cl  H     H                                     24 (Ex. 24)                                                                            6-CH(Me).sub.2                                                                              H      4'-Cl  H     H                                     25 (Ex. 25)                                                                            6-C(Me).sub.3                                                                               H      4'-Cl  H     H                                     30 (Ex. 30)                                                                            8-CH(Me).sub.2                                                                              H      4'-Cl  H     H                                     34 (Ex. 34)                                                                            6-F          8-F    4'-Cl  H     H                                     37 (Ex. 37)                                                                            6-F (-)isomer                                                                               8-F    4'-Cl  H     H                                     38 (Ex. 38)                                                                            6-F (+)isomer                                                                               8-F    4'-Cl  H     H                                     39 (Ex. 39)                                                                            8-Me (-)isomer                                                                              H      4'-Cl  H     H                                     40 (Ex. 40)                                                                            8-Me (+)isomer                                                                              H      4'-Cl  H     H                                     41 (Ex. 41)                                                                            8-F (-)isomer                                                                               H      4'-Cl  H     H                                     42 (Ex. 42)                                                                            8-F (+)isomer                                                                               H      4'-Cl  H     H                                     43      6-F          8-F    3'-Cl  4'-Cl H                                     44      6-F          8-F    2'-Cl  4'-Cl H                                     45      6-F          8-F    4'-OMe H     H                                     65 (Ex. 45)                                                                            6-F          8-F    2'-Cl  H     H                                     68 (Ex. 54)                                                                            6-F          8-F    3'-Cl  H     H                                     ______________________________________                                    


9. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier. 